DE3002292A1 - 4- (NAPHTHYLMETHYL) PIPERIDINE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF - Google Patents

Description

Our no. 22 653

Richardson-Merreil Inc. VJiI t on s C onnec ti cut »V.St„ A.

4- (NaphthylmethylX ^ piperidine derivatives _fl Process for their preparation and their use

The present invention relates to new derivatives of 4- (naphthylmethyl) piperidines and processes for their preparation. In particular, the present invention relates to novel naphthyl - piperidyl-ketones "" ^ - - (naphthyl) -4-piperidinmethanole and 4- (naphthylmethyl) piperidines _s which are used as chemical intermediates useful and their N- (u-benzoylalkyl) - *! And N ~ (j £-hydroxy-6> phenylalkyl) derivatives which causes as neuroleptic tranquilizers ₂ whose use no significant extrapyramidal side effects _s are useful "

4-piperidyl-l = and 2-naphthyl-ketonesdie as analgesics and anti-coagulants useful are _s are described in U.S. Patent No. 3,795,677. It has now been found that these compounds _s and its alkyl ₉ alkoxy halogen and _s trifluoromethylnaphthyl analogs as intermediates in the preparation of new "-A- (naphthoyl) -L-piperidyl7- _s A- (Naphthylhydroxymethyl) -l- piperidyl7- and A-naphthylmethyl-1 = piperidyl7-1-phenyl = 1-alkanones and -1-phenyl-1-alkanols are useful.

030034 / QS71

2- (l- and 2-Naphthyimethyl) piperidine, 2-piperidyl-isomers of the new 4- (naphthylmethyl) piperidine according to the present invention were as described by Koehler, et.al., Tetrahedron Lett.1977 (7) ₃₆₃₅ -638, reported to be formed in a rearrangement reaction, the production of 2- (1-naphthylmethyi) piperidine was described by L. Panizzon, Helv.Chim.Acta 27, 1748-1756 (1944). These isomers have not been found useful or useful as intermediates in the preparation of the novel neuroleptic compounds of the present invention

030034/0571

Tranquilizer described »

The new compounds of the general formula

(CH ₂ ) -Z - </

where η is an integer from 2 to 5 _S R ^e i ⁿ hydrogen atom, an alkyl radical _s an alkoxy radical _s a halogen atom or a trxfluoromethyl radical ₉ FL a hydrogen atom,) an alkyl radical, an alkoxy radical or a halogen atom _a X a carbonyl _{radical s} a hydroxymethylene radical or a Methylene radical and Z a carbonyl radical or a hydroxymethylene radical mean _a are as. antipsychotic agents useful. These antipsychotic compounds can be obtained by alkylating intermediates of formula II

? i!

wherein R and X have the meanings given above, are prepared. The connections of the Formula II are, with the exception of the compounds in which X is a carbonyl radical and R is a hydrogen atom, also new connections and are from

030034/0871

the

of the present invention includes / present invention also relates to the pharmaceutically acceptable acid addition salts and individual optical isomers of the compounds of the formulas I and II.

The compounds of formula I include 1- and 2-naphthyl derivatives of u / - ^ - (naphthoyl) -l-piperidyl7- _s <^ - {H- (naphthylhydroxymethyl) -l-piperidylJ- and ω-P \ - ( Naphthylmethyl) -l-piperidyl / -l- (4-subst.) Phenyl-1-alkanones of the formula III

-! I I

and 4-naphthoyl, 4- (naphthylhydroxymethyl) - and ² I- (naphthylmethyl) -o ^ - (ij-subst.) phenyl-1-piperdine alkanols of the formula IV

-IV

wherein n, X, R and R _{1 have} the meanings given above, their individual geometric and optical isomers and their pharmaceutically acceptable acid addition salts.

030034 / 0S71

The term alkyl radical as used herein means straight or branched chain alkyl radicals with 1 to ¹ l carbon atoms »Illustrative examples for.Alkyl radicals are the methyl radical _s ethyl radical _s propyl radical and tert» butyl radical »The term alkoxy radical means straight or branched-chain alkoxy radicals with 1 to 4 carbon atoms understood »Illustrative examples of alkoxy radicals are the methoxy radical _s ethoxy radical and isopropoxy radical» The term halogen atoms means fluorine atoms _a chlorine atoms or bromine atoms »

The substituent R can be located at any point on the naphthalene ring with the exception of the position occupied by the (X-piperidyl) substituent _s »

Preferred compounds according to the invention are the compounds of the formula I ₅ in which Z is a carbonyl radical and X is a carbonyl radical or a hydroxymethylene radical "Also preferred are compounds according to the _{invention", in which η = 3 "Further preferred embodiments of the present invention are compounds of the formula I 8 irorin R} represents a hydrogen atom or a halogen atom. Preferred embodiments of the present invention also include compounds of the formula I ₈ in which R is a halogen atom and preferably a fluorine atom »

Examples of the compounds of formula I are

4-A- (l-naphthoyl) -l-piperidyl7-l- ( ¹ »-fluorophenyl) -lbutanone,

butanone,

4-Z ¹ l- (6-chloro-2-naphthoyl) = l-piperidyl7-l- ⁽ⁱ i-fluoro = phenyl) -1-butanone,

3-Z "4" (l | -Methoxy-l-naphthoyl) -l-piperidyl7-l- (4-chloro = - phenyl) -1-propanone,

H-Pi- (2-naphthoyl) -l-piperidy UI- (4-methylphenyl) = l ~

butanone ₉
3Ö034 / Ö571

5- / ¹ I- (l-Methy l-2-naphthoyl) -l-piperidy 17-1 - (^ - ethoxyphenyD-1-pentanone,

ii - / ^ - ((l-naphthyl) hydroxymethyl) -l-piperidyl7-l- (4-methylphenyl) -l-butanone,

ⁱ i- / l '- ((2-naphthyl) hydroxymethyl) -l-piperidyl7-l-butanone -1 (4-fluorpheny1)

3-A - ((l-fluoro-2-naphthyl) hydroxymethyl) -l-piperidyl7-l-C ^ -fluorophenyU-l-propanone,

3-A - ((8-methoxy-2-naphthyl) hydroxymethyl) -l-piperidyl7-1-pheny1-1-propanone,

¹ IA - ((1-Naphthyl) methyl) -l-piperidy 17-1- (4-fluorophenyl) -1-butanone,

ⁱ »-A - ((6-chloro-2-naphthyl) methyl) -l-piperidyl7-l- ( ⁱ lchlorphenyl) -l-butanone,

6-A - ((2-Naphthyl) methyl) -l-piperidyl7-l- ( ¹ l-methylphenyl) -l-hexanone,

^ - / "(l-NaphthyDhydroxyniethynJ-c ^ -i ^ -fluorophenyD-lpiperidinbutanol,

M - / "(i | -Trifluoromethyl-2-naphthyl) hydroxymethyl7- ^c ^ - (il-fluorophenyD-1-piperidinebutanol, ⁱ l - /" (6-chloro-2-naphthyl) hydroxymethyl7-c ^ -phenyl-l-piperidine propanol ,

4- Z "(7-Isopropy 1-1-naphthy 1) hy droxyme thy U-oC- (4 -chlorphenyl) -l-piperidinepentanol,

4- (2-naphthoyl) -oC- (4-fluorophenyl) -l-piperidinebutanol, ^ - (^ - Brom-l-naphthoyD-oC-phenyl-l-piperidxnbutanol,

M8-methyl-1-naphthoyl) ^ - (4-chloropheny1) -1-piperidinopropanol,
l | - (6-chloro-2-naphthoyl) -oi- (4-fluorophenyl) -l-piperidinebutanol,

4 - / "(l-naphthyl) methyl7-o <: - (4-fluorophenyl) -1-piperidinebutanol,

4 _ / - (Jj-Trifluoromethyl-2-naphthyl) methyl7-oi- (4-methylphenyl) -l-piperidinebutanol,

030034/0571

-Isopropyl-l-naphthy I) methyl7 -c <- (^ l-methoxy phenyl) 1-piperidinepentanol. And

¹ I-Ci 3-ethoxy-2-naphthyl) methy Ij -o (- phenyl-1-piperidinopropanol.

The present invention also encompasses the pharmaceutically acceptable acid addition salts of the compounds of formula I, which are also effective as antipsychotics. Suitable salts are those of inorganic acids _s such as hydrochloric acid ₉ hydrobromic _s sulfuric acid, and phosphoric acid, carboxylic acids ^ such as acetic acid _s propionic _s glycolic acid ₀ lactic acid _s pyruvic acid _s malonic acid ₉ succinic _s fumaric _s malic _s tartaric acid, citric ₉ ascorbic _s maleic, hydroxymaleic _s dihydroxymaleic acid _s benzoic acid _s phenylacetic acid, ii-aminobenzoic acid j _{/ anthranilic acid s} cinnamic acid, salicylic _{acid s aminosaldcyclic acid s} 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and mandelic acid, and sulfonic acids such as methanesulfonic acid _s 2-hydroxyethanoic acid and p-toluene acid.

Novel compounds of formula I are anti-psychotic agents, which, if they are useful alone or in the form of pharmaceutical preparations which contain the novel compounds in combination with a pharmaceutical carrier as neuroleptic _s tranquilizers in warm blooded animals. Neuroleptic tranquilizers are _s such as schizophrenia, or show for the treatment of patients who have symptoms of psychosis by severe anxiety, severe excitation or aggressiveness, useful. Such agents have a tranquilizing effect on psychomotor activity because they induce a state of general rest in the patient without inducing sleep. Patients eligible for treatment with antipsychotic preparations containing the compounds of the invention

+ 4-hydroxybenzoic acid

030034/0571

Formula I are suitable include warm-blooded animals such as birds, e.g. turkeys and chickens, and mammals, e.g. Mice, rats, dogs, cats, horses, pigs, cattle and sheep, and including humans.

Pharmaceutical preparations _s contain the compounds of formula I according to the invention may be in solid or liquid form, such as, capsules present as tablets _s powders, solutions, suspensions or emulsions, and parenteral _9, for example intraperitoneally, intramuscularly or subcutaneously, or topically, for example, can be administered orally, transdermally or administered transmucosally. The quantity containing an effective amount of the novel compound, which is provided in a dosage unit, and the nature and quantity of the pharmaceutical carrier vary widely according to the nature of the pharmaceutical preparation and the body weight of the patient to be treated. Treatment of a patient in need is from 0.005 to 100 mg / kg of patient body weight per day in order to produce the desired tranquilizing effect. In a human, this level of tranquilization can be achieved by means of an antipsychotic preparation in the form of tablets containing from 0.5 to 300 mg of the active compound and a suitable pharmaceutical carrier, administered from 1 to ¹ times daily. Smaller dosage units will be required in order to achieve a comparable neuroleptic effect in smaller species of living being.

The compounds of general formula I, together with suitable pharmaceutical carriers, can be in the form of solid dosage units, such as tablets, capsules and powders, in the form of a suppository or embedded are present in a polymeric matrix. In the preparation of

030034/0 571

of solid dosage units, it may be desirable to _see the compound to be used to mikronisiereno ¹¹¹ fixed unit dosage forms, the compounds with conventional carriers _9, for example, binders _s as Akaziengummij, corn starch or gelatin, disintegrants _s such as corn starch ^ guar gum (guar gum), or alginic acid ₃ lubricants ,, as Stearic acid or magnesium stearate ^ and inert fillers ^ such as lactose, sucrose or corn starch combined iverden =

The compounds of general formula I can also be used as liquid suspensions or solutions _s a sterile liquid such as an oil _s water _s an alcohol or mixtures thereof _B with or without the use of a pharmaceutically suitable surface-active agent _s suspending agent or emulsifier _s for oral _s topical or use parenteral administration _{s be} administered »

For liquid preparations, the compounds of formula I may suitably with oils _s, for example, non-drying oils _s such as peanut _s sesame oil and olive _oil's fatty acids such as oleic acid and isostearic acid and fatty acid ester ^ such as isopropyl myristate and fatty acid glycerides ₉ with alcohols _s such as ethanol ₈ isopropanol and propylene glycol with Oil hydrocarbons _s water or mixtures thereof are formulated ο

Peanut oil and sesame oil are particular in the manufacture of formulations for intramuscular injection Useful, oils can also be used in the manufacture of Soft gelatin type formulations and suppositories can be used.

030034/0871

. 300229

Water, saline, aqueous dextrose and related sugar solutions and glycerols such as polyethylene glycol can be used in the preparation of _: liquid formulations which suitably contain suspending agents such as pectin, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives .

For example, when 4-A- (2-naphthoyl) -1-piperidyl) -1- (4-fluorophenyl) -1-butanone hydrochloride administered intraperitoneally to mice at a dose of 0.3 mg / kg was the total toxicity of d-amphetamine at 50? the Mice inhibited according to the methods described by J. Burn et al., Arch. Int. Pharmacodyn. 113, (1955) 'pages 290-295 demonstrating antipsychotic activity, while a dose of 1.0 mg / kg of the known Tranquilizers Chlorpromazine to achieve a similar degree of reaction was required. In the same Way, the compounds according to the invention show neuroleptic Efficacy by inhibiting pernicious preening in mice exposed to the by A. Kandel et al., Ped. Proc, 19 (1, part 1), 1960, 24.

The neuroleptic effectiveness of these compounds is derived from a decreased propensity to produce extrapyramidal Side effects in patients who are active with neuroleptic disease Dose treated compared with known antipsychotic agents, accompanied. if i} - / II- (2-naphthoyl) -l-piperidyl7-1- (4-fluorophenyl) -lbutanone hydrochloride administered intraperitoneally to mice, a dose of 16.6 mg / kg was required at 50? of the mice produced according to the general method that by P.A.J. Jan'ssen et al., in Arzneimittel-Forsch. 10, 1960, Page 1003, described, were tested to counteract the behavioral effects of apomorphines ^,

030034/057 1

while only I ₉ 4 mg / kg chlorpromazine to achieve a similar effect required _s were indicative of a reduced extrapyramidal effect of the compounds of the invention "

The compounds of formula I are prepared by alkylating the intermediate compounds of formula II. The compounds of the formula II ₉ with the exception of 1- and 2-naphthyl-4 = piperidyl-ketone _s, ie of compounds of the formula II. In which X is a carbonyl _{radical and R is a hydrogen atom, s} are also new and are encompassed by the present invention

The compounds of formula II include 1- and 2-naphthyl ^ -piperidyl-ketones of the formula V

C = O

o <- (l- and S-naphthyD-Jl-piperidinemethanols of the formula VI

CHOH

- -.Vl

and their individual optical isomers and HT (I- and 2-naphthyl) methyl7piperidines of the formula VII

03003 4/0571

Vi I

wherein R has the meaning given above, and the acid addition salts thereof.

Examples of compounds of formula II include 1-Napht hy 1-4-piperidyl ketone ,, 2-naphthyl-4-piperidyl ketone _s 6-chloro-2-naphthyl l ^1-piperidyl ketone _J 4-methoxy-l ~ naphthyl-4-piperidyl-ketone, 1-methyl-2-naphthyl- ⁱ } -piperidyl-ketone _s 1-fluoro-2-naphthyl-4-piperidyl-ketone _s S-methoxy ^ -naphthyl-Ij-piperidyl-ketone ", Jj-trifluoromethyl-2 ~ naphthy 1-4 -piperidyl-ketone _s 7-isopropyl = 1-naphthyl-4-piperidyl-ketone _s ° C- (1-naphthyl) -4-piperidinmethanol _s o < - (2-Naphthyl) - * J »piperidinemethanol _s o6- (6-chloro-2-naphthyl) - ⁱ 4-piperidinemethanol ₅₁ oi-C ^ -Methoxy-l-naphthylJ - ^ - piperidinmethanolj o <.- (l- Methyl-2-naphthyl) - ⁱ } -piperidinemethanol ₃ ^£ ^ - (l-fluoro-2-naphthyl) - ⁱ i-piperidinmethanol ₃ o <- (8-methoxy-2-naphthyl) - ⁱ } -piperidinmethanol _s o4_ ( 4-trifluoromethyl-1-naphthyl) -4-piperidinemethanol, c <- (7-isopropyl-1-naphthyl) -4-piperidinemethanol _s I \ -C { 1-naphthyl) methyl7piperidine _s

4-Z * (2-naphthyl) methyl7piperidine, 4-Z "(6-chloro-2-naphthyl) methyl7piperidine ₅

030034/0 ß71

Methoxy-1-naphthyl) methyl-7-piperidine, it-Al-methyl-2-naphthyl) methyl, 7-piperidine _s iJ ~ Z '(1-fluorine-2-naphthyl) ynethyl-7-piperidine ₃ 4 _ / - (8-methoxy-2-naphthyl) methyl-7-piperidine _s 4 - / "(M-trifluoromethyl-1-naphthyl) methy: i7piperidine and 4-1 / ₂ (7_l opyl-1-naphthyl) methyl7piperidino

Compounds of the formula Vja ₉ in which Rp is a hydrogen atom ^ Salogenatonij, an alkyl radical or an alkoxy radical ₉ and _s when Rp has a meaning other than hydrogen _s Rp is bonded to the 2- _s H- or 7-position of the naphthalene skeleton _s when the M-piperidyl = carbony! Group is arranged in the 1-position _s and R _? is bound to the 6 position of the Naphthalinskelettes ₂ when the M-Piperidylcarbonylgruppe in the 2-position can ists arranged directly by the Friedel-Crafts acylation of an appropriate naphthalene derivative by the hydrogen halide salt of an M-piperidinocarbonyl-halide _{s s} is as shown below

C Halo Lewis-

-Acid

O acid. H-HaIo> R.

H C = O

SQuSk / UbI ι

- 30 -

wherein halo represents a chlorine atom or a bromine atom.

If a! -Substituted naphthalene derivative of the Friedel-Crafts reaction is subjected, the predominant product is a 1,4-disubstituted product. When a 2-substituted Naphthalene derivative is subjected to the Friedel-Craft reaction, is the predominant product a 1,2-, 2,6- or 1,7-disubstituted product. The amounts of the various isomers of the compounds of Formula V ^ a, including the quantities of different unsubstituted 1- and 2-naphthyl-4-pipefidyl-ketones can by varying reaction conditions, as they are in General von P. H. Gore in Friedel-Crafts and Related Reactions, Volume IH (G. A. Olah, Ed., Inter science Publishers), 1964, pages 1 - 382, varies will.

The aforesaid reaction can be carried out in a variety of solvents such as nitrobenzene, chlorinated hydrocarbons such as chloroform and tetrachloroethane, or carbon disulfide and catalyzed by a variety of Lewis acids such as aluminum chloride, boron trifluoride, hydrofluoric acid or tin IV chloride. The amount of Lewis acid used in the reaction varies on a molar basis from 1-8 times and is preferably three to four times more than the amount of the 4-piperidine carbonyl halide. A preferred method is to combine the reactants in the presence of a solvent in an ice bath, slowly add an excess of aluminum chloride with stirring, and maintain the temperature below 35 ° C. After completion of the addition the temperature is 10 minutes to 6 hours, preferably 10 minutes to 30 minutes, from 25 ° C to 90 ⁰ C, preferably 50 ⁰ C to 90 ° C is increased. The reaction mixture is made with water and ice

030034/0571

U U 4, i. \ j

decomposed and then strongly basified by treatment with a 50 $ aqueous solution of sodium hydroxide under cooling The basified reaction mixture is then extracted with a suitable solvent such as toluene ;, chloroform or chlorobenzene "The organic extract is dried _s filtered, and _s is concentrated using a base of the formula Va is obtained. Which can be converted into an acid addition salt by reacting a suitable acid with the base according to generally known processes »

The corresponding (3C (naphthyl) -4-piperidinmethanole of formula VIa and ^ -Naphthylmethylpiperidine of formula VIIa _s can be manufactured by the methods described above by selective reduction of the ketones of formula Va _s are prepared "for the catalytic reduction may be a Ketone of the formula Va ZoBo can be dissolved in a solvent such as acetic acid _s ethyl acetate or a lower aliphatic alcohol _s such as methanol or isopropanol and the solution in the presence of hydrogen at a pressure of about 1 to about 4 bar and room temperature ₉ ie about 20-25 ° C _{S s} are stirred in the presence of a suitable catalyst and at least one equivalent of an acid is added to hydrogen gas until the theoretical molar amount = under mild conditions, "as such ₉ when the catalyst is a platinum, platinum oxide = · or rhodium catalyst ₉ is an equivalent of hydrogen absorbed _s and the corresponding alcohol of formula VIa is prepared U nder stringent Bedingungenj how such a _s when the catalyst of palladium or copper-chromium Oxsd consists ₉ a strong acid _s such as hydrochloric acid ₉ sulfuric acid or perchloric acid is added and the reaction temperature optionally vcän to a temperature in the range 25 - 100 ° C is increased, " two equivalents of hydrogen gas are

030034/0571

BADORfGlNAL - "Λ

sorbed and is a 4-Naphthylmethy! piperidin der Formula VIIa made.

Alternatively, the ketone of formula Va can be selectively reduced by reaction with a suitable chemical reducing agent. If the ketone is refluxed for 1-5 hours with a metal hydride, e.g. lithium aluminum hydride or diborane, in ether or for about 1/2 hour to 8 hours at a temperature of ⁰ ° C. to the reflux temperature of a lower aliphatic alcohol used as a solvent, such as methanol or ethanol; is reacted with a metal borohydride, such as sodium borohydride or potassium borohydride, one C- (naphthyl) -4-piperidinemethanol of the formula VIa is obtained. A 4- (naphthylmethyl) piperidine of formula VIIa can be substituted by 1 to H hours of heating the ketone of formula Va with zinc amalgam in the presence of about 2 to about 10 equivalents of hydrochloric acid, wherein the hydrochloric acid as dry hydrogen chloride in an aprotic organic solvent such as E. ether or benzene or als.eine concentrated aqueous solution is added in the presence of an organic solvent, under reflux or by 2 - hydrate hydrazine 200 ⁰ C and with a strong base - lOstündiges heating the ketone of formula Va at a temperature of about 90 , for example an alkali metal alkoxide such as sodium ethoxide., odojeinem alkali metal hydroxide such as potassium hydroxide; and optionally a platinum metal catalyst followed by conventional work-up.

Further reagents suitable for the selective reduction of a ketone to an alcohol or to an alkari are obvious to those skilled in the art. The reduced bases of the formula VIa and the

030034/0571

Formula Vila can be made by reacting with a suitable Acid can be converted into the acid addition salts according to generally known methods.

The general process of Friedel-Craftfs preparation of the compounds of the formula H ₃ in which Rp is a hydrogen atom, _{s is} a halogen atom, _{s is} an alkyl radical or an alkoxy radical and ₄ when R _{2 is} other than a hydrogen atom, _{9 is} the radical of the formula

and R _{2 are arranged} in the 1 _S 4- _S 1 _S 2- _S 2 _S 6 or l _s 7 ~ position of the naphthalene ring _a is represented by the general reaction scheme A:

Reaction scheme A - Friedel-Craft's synthesis of the compounds of the formula II

LewIs- --- -

C = O

030034/0571

Each of the compounds of the formula II can by means of reactions of the Grignard reagents of the formula 1 are prepared by reacting bromine and xodnaphthalenes of formula 2 with magnesium metal according to

Mg

wherein R is as defined above and Y is a bromine atom or an "iodine atom. Compounds of formula 2 are well known in the art and can be prepared by known methods. The naphthyl halide of formula 2 is from 1 36 hours at reflux temperature with magnesium powder or rings in an ether solvent such as ethyls ether or tetrahydrofuran, and optionally a catalyst such as lodjgerührt. a pyridine _derivative? such as 4-pyridine-carbonitrile, 4-pyridine carboxaldehyde or 4-halomethylpyridine is added to the resulting Grignard reagent and the resulting The mixture is refluxed for 2-8 hours. The resulting adduct is decomposed by the addition of a cold, dilute, aqueous mineral acid solution or, preferably, a saturated, aqueous ammonium chloride solution Formula 1 with 4-pyridine carbonitride I obtained a naphthyl-4-pyridyl-ketone of the formula 4. The reaction of a naphthyl-Grignard reagent of the formula 1 with 4-pyrxdincarboxaldehyde gives a c <- (naphthyl) -4-pyridinemethane of the formula 5 and the reaction of a napthyl-Grignard reagent of the formula 1 with a 4-halomethylpyridine leads to a

030034/0571

k- (naphthylmethyl) pyridine of formula 3. The relative positions of the R and pyridylmethyl s substituents in the compounds of formulas 3, _5, 4 and 5 are the same as those of the R and halogen substituents of the compound of formula 2 _S from each other the Grignard reagent was prepared.

The pyridyl compounds are selectively catalytically reduced, with 4 ~ (naphthylmethyl) pyridines of the formula 3 _S ^ - (naphthylmethylpiperidines of the formula VII and from naphthylpyridyl ketones of the formula 4 and «^ - (naphthylJ - ^ - pyridinemethanols of the formula 5 either E4 (naphthyl) -4-piperidinmethanole of formula VI or ¹ I- (Naphthylmethylpiperidine of formula VII _5, depending on the chosen reaction conditions are obtained _s "" the catalytic reduction under mild conditions ₉ as described above, provides compounds of formula VII 4- (Naphthylmethyl) pyridines with consumption of three equivalents of hydrogen gas and compounds of the formula VI from (^ - (NaphthylJ-ll-pyridine = methanols with consumption of three equivalents of hydrogen gas or from naphthyl- ^ i-pyridyl ketones with consumption of four equivalents Hydrogen gas Catalytic reduction under more severe conditions as described above " leads to 4- (naphthylmethyl) piperidines of the form VII from oC- (Napthyl) -4 ~ pyridinemethanols with consumption of four equivalents of hydrogen gas or from naphthyl-Jl-pyridyl-ketones with consumption of five equivalents of hydrogen gas. Alternatively, a prepared as described above oil (naphthyl) -4-piperidinemethanol of formula VI by about 6 to about 24 hours of heating its alcoholic solution under reflux with an aqueous solution of a strong acid such as hydrochloric acid _{9 s} sulfuric acid or phosphoric acid, adjusting the pH of the solution with 10 tigern sodium hydroxide to about ^ Extract the dehy-

0 3 0034/0571

dratisierten intermediate \ in an organic solvent and, after evaporation of the solvent, catalytically reducing the dehydrated intermediate unterjmilden conditions as described above, dehydrated under consumption of one equivalent of hydrogen gas, wherein a compound of formula III, as shown below, ER · will hold:

Vl 6 VM

If a naphthyl-piperidy ^ JL- ^ eton of the formula V is to be produced, daso <. - (Naphthyl) -4-piperidinemethanol of the formula VI oxidized by reaction with a suitable oxidizing agent according to methods known in the art. Oxidizing agents which are able to convert a secondary alcohol of the formula VI into a ketone of the formula V include, for example, chromic acid, chromic anhydride, sodium dichromate and lead tetraacetate in a suitable solvent such as acetic acid, sulfuric acid or pyridine, and potassium permanganate and manganese dioxide in a suitable solvent such as petroleum ether, benzene, methylene chloride or water. The reaction temperature can vary from 0 to 100 ^° C. and is preferably room temperature. The reaction time can vary from 10 minutes to a day and is preferably 1/2 hour to 1 hour.

030034/0571

A naphthylmethylpiperidine of the formula VII can, for example, by base-catalyzed hydroxylation with molecular oxygen in accordance with the general method described by J «Gutzwiller et al» in JcAmoChemoSoc. 92 _s 204-205 (1970), can be converted into a piperidinemethanol of the formula VI.

Naphthyl-4-piperidyl-k'etone of formula V may also be prepared by reaction of a naphthyl Grignard reagent of Formula 1 with 4-piperidinecarbonitrile or its N-protected derivative _s such as N-acetyl-4-piperidinecarbonitrile or N-trifluoroacetyl-Jj -piperidine carbonitrile can be obtained under the conditions described above with the further step of hydrolyzing the product to remove the nitrogen protecting group · Naphthyl-4-piperidyl ketones of the formula V ₈ which are prepared in this way, can also be selectively reduced to to prepare the o (- (naphthyl) - 4-piperidinemethanols of the formula VI and the 4- (naphthylmethylpiperidines of the formula VII) ο

The general method for the preparation of the intermediate compounds of the formula II by means of a Grignard reagent is represented by the general reaction scheme B _s in which Q is a radical of the formula _{-CN 5} -CHO Or-CH ₃ -HaIo and R., a hydrogen atom or a protective group and R has the meaning given above, "represented"

030034/0571

Reaction scheme B Grignard synthesis of the compounds of the formula II

03003.4 / 057

4- (Naphthylmethyl) pyridines of the formula 3 _S Naphthyl- ¹ ! - pyridyl-ketones of the formula 4 or C ^ - (naphthyl) pyridinemethanols of the formula 5 can also be prepared by other methods known in the art, for example by oxidation of the corresponding tetralin -Derivates ₉ as described in British patent IIIOO87 _s and by reacting organometallic reagents other than the naphthyl-Grignard reagents described herein, for example by reacting 4-lithiopyridine, as described by JP Wilbaut et, al O ₂ Rec.Trav. Chim, 74, _P 1003-1020 (1955) described are made _s or organosodium or organopotassium reagents, and can be selectively reduced and optionally j, as described above., be oxidized to give the compounds of formula II are obtained.

Are free bases of the formula II _{s s} were prepared by any of the methods described above may in the Saureaddtionssalze by reaction with a suitable acid according to well known procedures converted =

The compounds of formula I are prepared by reacting a piperidine derivative of the formula II in the presence of an excess of an acid acceptor ₉ such as Natriumbicarbonatj potassium bicarbonate _s sodium carbonate or potassium carbonate, and optionally a small amount of potassium iodide in a suitable solvent with a slight excess of a ω -haloalkyl phenyl-ketone or a u-halo-1-phenyl-1-alkanol of the formula 7 prepared = If desired, instead of the mineral basic acid acceptor, two or more equivalents of a piperidine derivative of the formula II according to the

030034/0571

3Ä

binding 7 can be used. The compounds of formula I can also be prepared from the acid addition salt of the compound of formula II by reacting the Säureadditionssal _z in the presence of at least two equivalents of the mineral basic acid acceptor, with a compound of the formula. 7 The reaction mixture can be reacted over a wide range of temperatures. In general, a reaction temperature of from about 20 ° C. to 180 ° C. is used. The reaction is carried out over a period of 1 to ¹ Y days, being able to be collected during this time any of these developed water. Examples of solvents suitable for this reaction are toluene, xylene, chlorobenzene, methyl isobutyl ketone and lower aliphatic alcohols such as ethanol, propanol and butanol.

After the reaction is complete, the product is isolated in a conventional manner, e.g., the reaction mixture can filtered and the solvent removed with isolation of the product. Alternatively can the filtrate with the ethereal solution of a suitable mineral or organic acid are treated, whereby the corresponding salt of the product is obtained. The crude product is filtered off, purified by recrystallization and dried. Suitable solvents for the recrystallization are e.g. lower aliphatic alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and butanone, Esters such as ethyl acetate, ethers such as diethyl ether, and combinations thereof.

030034/0571

The general method for the preparation of the compounds of Formula I can be by the following Reaction scheme

χ + tfalo- (CH ₂ ) -Z- / y-Ri gases

L ·.

where HjR ₃ R ^ ₃ X and Z are as defined above and halo is a reactive halogen atom _s such as a bromine atom _s a chlorine atom or an iodine atom «are represented«

The compounds of the formula 7 are commercially available or can be prepared by methods known in the art. Compounds of the formula 7 _S in which Z denotes a radical of the formula C = O _s can be prepared, for example, _s that the appropriate ω -haloalkanoyl halide is present in the presence a Lewis acid ₉ such as aluminum chloride with a (substituted) benzene or by reacting e ^ n (4-substituted) phenyl Grignard reagent with a suitable OJ-haloalkanonitrile. The compounds of the formula 7 _S in which Z is a radical of the formula CHOH ₉ can be obtained by reduction ₉ by any of the measures described above for the reduction of a ketone to an alcohol ₉

030034/0571

the corresponding 1- (4-substituted) phenyl haloalkanones of formula 7, which were prepared as described above, or by reaction of a (^ -substituted) Phenyl-Grignard reagents can be prepared with a suitable VtJ -halogenalkanaldehyde.

The compounds of the formula III in which η = 2 can can also be prepared by combining any of the compounds of formula II with an appropriate acetophenone and formaldehyde.

1-piperidine canols of the formula IV »in which X is a hydroxymethylene or denotes a methylene radical, can be prepared by reducing alkanones of the formula III. Compounds of the formula III in which X is a hydroxymethylene radical or a carbonyl radical result after reduction, compounds of the formula IV in which X is a hydroxymethylene radical; Compounds of formula III, in which X is a methylene radical, compounds of the formula IV in which X is a methylene radical will result. Suitable methods of reduction include any chemical or catalytic method of reduction, as described above for the reduction of a ketone to an alcohol, e.g., by the catalytic Reduction of a solution of a ketone of the formula III with hydrogen gas in the presence of a catalyst such as platinum, platinum oxide or rhodium under mild conditions, or by reducing the ketone by a Metal hydride such as lithium borohydride or diborane, or a metal borohydride such as sodium borohydride. If X is a Hydroxymethylene radical means, individual diastereomers can by methods such as fractional crystallization, which are well known in the art.

030034/0571

The compounds of the formula I ₃ which were prepared in the form of the free base ₉ can be converted into their acid addition salts by reaction with a pharmaceutically acceptable acid.

The optical isomers of the present invention optically active compounds may be prepared by any suitable dissolving agent is separated = For example, the optical isomers can of compounds of formulas I or II, wherein one or both of X and Z is a hydroxymethylene _s are using a (+) - or (-) - Binaphthylphosphoric acid derivative or a salt of this derivative and an optically active base by the method described by R. Viterbo et al "in Tetrahedron Letters 1971 (48) _s pages 4617-4620.? described method are separated «

The following examples serve to explain the present invention »

example 1 ^ -Naphthyl - ^ - piperidyl ketone hydrochloride

A slurry of 99 g of naphthalene (0 _s 75 mol) and 96 g of isonipecotinic acid chloride hydrochloride (0 _s 5 mol) in tetrachloroethane was _{admixed with 200 g (1 S} 5 mol) of aluminum chloride over a period of 10 minutes. The reaction mixture was 10 minutes at room temperature, allowed to stand _{s s} then decomposed by _it's poured over ice water with a 50 $ NaOH solution made basic, and extracted with diethyl ether. The ethereal layer was dried over magnesium sulfate, _s

030034/0571

filtered and with ethereal. Treated HCl. The resulting oil was dissolved in heated methanol with Treated charcoal, filtered and diluted with butanone. The methanol was removed by distillation and more butanone added than necessary. The solution was chilled overnight. The resulting solid was filtered off and recrystallized from methanol-butanone to give the desired product. Melting point 251-253 ° C

Example 2 l-naphthyl - ^ - piperidyl ketone hydrochloride

The mother liquor remaining after crystallization of the 2-naphthyl-4-piperidyl-ketone hydrochloride according to Example 1 was mixed with a large excess of butanone. The resulting solution was reduced in volume to approximate the original volume and cooled. The resulting solid was filtered off and recrystallized from methanol / butanone to give the 1-naphthyl isomer.
Melting point 192-194 ° C.

Example 3 6-chloro-2-naphthyl-4-piperidyl ketone

A stirring suspension of 3 »15 g (19.4 mmol) of 2-chloronaphthalene and 4.46 g (24.2 mmol) of 4-piperidine carbonyl chloride hydrochloride in 60 ml of nitrobenzene was gradually added to 9 _S 7 g (73 mmol) of aluminum chloride were added. The mixture was ^{heated to 65-7O 0} C for 2 hours and then cooled. The reaction mixture was with

030034 / 0B71

Ice water and concentrated HCl are added. The solid bodice shock was partitioned between aqueous' solution of sodium hydroxide and ether and the organic phase _s was concentrated with brine (brine), dried _s dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from cyclohexane _s wherein 6-chloro-2-naphthyl-4-piperidyl ketone was obtained.
Melting point 98-100 _s 5 ° C.

Example 4 6-chloro ° 2-naphthyl-4-piperidyl-ketone hydrochloride

Prepared in Example 3 6-Chloro-2-naphthyl-4- • piperidylketon was treated with an excess of HCl ₂₁ dissolved in ether and converted _{s s} recrystallized from absolute ethanol to give 6-chloro-2-naphthyl piperidylketon ^4-1 hydrochloride was obtained. Melting point ⁰

Example 5 2-chloro-1-naphthyl-4-piperidyl-ketone hydrochloride

The acidified piltrate prepared in Example 3 was extracted with ether to remove the nitrobenzene solvent and made strongly basic with NaOH. "The solution was extracted with ether / benzene, and the organic layer was dried over sodium sulfate and concentrated in vacuo" The residue was 4-piperidyl ketone hydrochloride acidified with HCl and from butanone / methanol and recrystallized from absolute ethanol to _s being 2-chloro-l-naphthyl was obtained.

"0 300 34/0 5-71

Example 6 ^ -Bromo-1-naphthyl-4-piperidyl-ketone

When 1-bromonaphthalene was used in place of 2-chloronaphthalene in the procedure of Example 3, ¹ J-BrOml-naphthyl-4-piperidyl-ketone was obtained.

Example 7 t <- (l-naphthyl) -4-pxperidinmethanol hydrochloride

To a solution of 60 g (0.22 mol) of 1-naphthyl-4-piperidyl ketone hydrochloride in 500 ml of methanol was gradually added 35 g (0.65 mol) of potassium borohydride with stirring in an ice bath, and the mixture was reacted for 18 hours . The mixture was concentrated in vacuo, the residue partitioned between chloroform and water, and the organic phase dried over magnesium sulfate, filtered and the solvent removed in vacuo to give ^ (- (l-naphthylJ - ^ - piperidinemethanol, which was dissolved in chloroform and an excess of dry HCl bubbled into the solution, and the resulting precipitate was recrystallized from methanol / butanone to give oC-il-naphthylJ-JJ-piperidinemethanol hydrochloride.
Melting point 219-221 ⁰ C.

Example 8 <X- (2-naphthyl) -4-piperidinemethanol ~ hydrochloride

In the procedure of Example 7, the l-naphthyl-4-piperidyl ketone replaced by 2-naphthyl-4-piperidyl ketone,

030034/057

thus became - ^ - NaphthyD-JJ-piperidinemethanol hydrochloride obtain"

Melting point

Example 9

α - (6-chloro-2-naphthyl) -4-piperidinemethanol

3, ¹ y? g (2 _S 7 mmol) of (6-chloro-2-naphthyl) - ^J 4-piperidyl ketone hydrochloride were suspended in 200 ml of absolute ethanol and treated with I ₉ 5 g ⁽¹ I mmol) of sodium borohydride "The reaction mixture was l8 hours stirred and concentrated in vacuo. The residue was washed with water trituriertgund aqueous sodium hydroxide was added to _s being a basic solution _s was obtained which was extracted with toluene / methylene chloride. The organic phase was washed _s with brine dried over magnesium sulfate filtered and concentrated in vacuo _{9 s} wherein concentrated OC (6-chloro-2-naphthyl) -4-piperidinemethanol was obtained "

Example 10

q- ( ¹ y -Bromo- 1-naphthyl) -4-piperidinemethanol

If in the procedure of Example 9 instead of 6-chloro-2-naphthyl-4-piperidyl-ketone hydrochloride ¹ I-BrOm-1-naphthyl-I-piperidyl-ketone was used ₃ then _a - (4-bromo-1- naphthyl) -4-piperidinemethanol obtained »

030034/0571

kl ·

- yr-

Example 11

q- (4-Trifluoromethyl-2-naphthyl) -4rpiperidinemethanol hydrochloride

A suspension of 2.5 g (0.1 mol) of magnesium in 20 ml of tetrahydrofuran was with an iodine crystal and a solution of 27.5 g (0.1 mol) of 1-trifluoromethyl-3-bromonaphthalj.n in 25 ml Tetrahydrofuran added. The mixture was refluxed for 1 hour with stirring, whereupon 10.7 g (0.1 mol) of 4-pyridinecarboxaldehyde dissolved in 50 ml of tetrahydrofuran; were gradually added and heated for an additional 3 hours. The reaction mixture was decomposed with saturated aqueous ammonium chloride solution and extracted with ether. The organic phase was washed with sodium carbonate, dried over sodium sulfate and filtered. The ether was evaporated and the resulting ct- (4-trifluoromethyl-2-naphthyl) -4-pyridinemethanol was dissolved in 150 ml of acetic acid and stirred in a Parr apparatus in the presence of 1.5 g of platinum oxide. Hydrogen gas was introduced and the reaction was continued until 3 moles of hydrogen gas had been consumed at _{0 sec.} The mixture was filtered and the solvent was removed in vacuo. The remaining residue was treated with an excess of HCl in ethereal solution, a- (4-trifluoromethyl-2-naphthyl) -4-piperidinemethanol hydrochloride being obtained.

Example 12

^ Trifluoromethyl ^ -naphthyl - ^ - piperidyl-ketone hydrochloride

A strongly cooled, stirred solution of 124 g (0.4 mol) of α- ( ¹ J-Tr if luormethy 1-2-naphthyl) -4-piperidinemethanol-

030034/0571

hydrochloride in 600 ml of acetic acid, 40 ml of 25% sulfuric acid and 72 ml of water were added to 26.5 g (0.27 mol) of chromium trioxide in 30 ml of acetic acid with stirring over a period of 1.5 hours, during which time a further 20 ml of water were added "The mixture was stirred for 1/2 hour at a temperature of less than 9 ° C." The solvent was removed under vacuum and the residue was treated with excess sodium hydroxide and extracted with ether and with chloroform. The combined extracts were washed with water, dried over magnesium sulfate and filtered. The Piltrat was extracted with further chloroform and ethereal HCl "The resulting precipitate was filtered off and recrystallized from isopropyl alcohol to give 4 _{s-trifluoromethyl-2-naphthyl-4-piperidyl} ketone hydrochloride was obtained.

Example 13

ⁱ } - [(4-Trifluoromethyl-2-naphthyl) methyl-3-piperidine hydrochloride

If palladium was used in place of platinum oxide in the procedure of Example 11, 4- [(^ -trifluoromethyl-2-naphthyDmethyljpiperidine hydrochloride manufactured.

Example 14

g- (4-chloro-1-naphthyl) - * t-piperidinemethanol hydrochloride

A flask containing 1.8 g (72 mmol) of magnesium turnings and 20 ml of anhydrous ether containing nitrogen, 10 drops of ethyl bromide were added. The ether was taking Heated to reflux and within 30 minutes a solution of 10 g (50 mmol) of l-bromo-JJ-cTilornaphthalL η

030034/0571

-yS-

in 150 ml of dry ether was gradually added, followed by continued refluxing for 8 hours. 60 g (58 mmol) of 4-pyridine carbonitrile in 100 ml of benzene was gradually added and the solution became
Heated under reflux for 3 hours. The adduct was
decomposed by addition of saturated ammonium chloride solution. The resulting ^ - (Ji-chloro-1-naphthoyDpyridine was extracted into ether and the organic phase was washed with brine and over magnesium sulfate
dried. The ether was removed in vacuo and the residue was dissolved in methanol and reacted
reduced with 200 mmol of hydrogen gas in the presence of a rhodium catalyst. The catalyst was filtered off, an excess of alcoholic hydrochloric acid was added and the solution was concentrated in vacuo. The residue was recrystallized from isopropanol to give "- (^ - chloro-1- 'naphthyl) -4-piperidinemethanol hydrochloride.

Example 15

4 ~ C (^ - chloro-1-naphthyl) methylpiperidine hydrochloride

250 ml of 6N hydrochloric acid were mixed with 27 ₃ 6 g (O ₅ I mol)
cx-C ^ -Chlor-l-naphthyD- ^ l-piperidine-methanol and for
Formation of a clear solution of sufficient $ 95
Ethanol added. The solution was heated under reflux for l8 hours _s cooled and basified with sodium hydroxide 10 $. The mixture was then extracted into toluene and the organic phase was washed with brine _s GEX-jaschen dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in acetic acid

030034/0571

and with hydrogen gas in the presence of a Parr apparatus shaken by 0.5 g rhodium / carbon at room temperature, until 0.1 mol of hydrogen was absorbed = the catalyst was filtered off, an excess of alcohol Hydrogen chloride was added and the solution was concentrated in vacuo. The residue became from methanol recrystallized with 4 - [(4-chloro-1-naphthyl) methyl] piperidine hydrochloride was received "

Example 16 S-methyl-l-naphthyl - ^ - piperidyl-ketone-hydrochloride

A solution of 10.0 g (45 mmol) of 1-bromo-8-methy1-naphthalene in 5 ml of ethyl ether gradually became a stirred mixture of 1.2 g (50 mmol) Magnesium added in 30 ml of anhydrous ether »Das The mixture was stirred under reflux for 1 hour and a solution of 6.0 g (43 mmol) of 1-acetyl - ^ - piperidine carbonitrile in 10 ml of tetrahydrofuran xv was slowly added = Das The mixture was stirred for 16 hours, an excess of saturated aqueous ammonium chloride solution was added and the mixture was heated on a steam bath for 3 hours = After cooling, the mixture was extracted with toluene and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 20 ml of ethanol and made basic with sodium hydroxide. The solution was extracted into toluene = by the

/ drier
Organic phase was blown hydrogen chloride, whereby S-methyl-1-naphthyl - ^ - piperidyl-ketone hydrochloride was obtained.

030034/0571

Example 17

4- [(3 ~ ethoxy-2-naphthyl) methyl-3-piperidine hydrochloride

A suspension of 2.5 g (0.1 mol) of magnesium in 20 ml of tetrahydrofuran was gradually mixed with a solution of 25 g (0.1 mol) of 2-bromo-3-ethoxynaphthaÜη in 25 ml of tetrahydrofuran. The stirred mixture was refluxed for 1 hour. A solution of 1.4 g (0.1 mol) of 4-chloro-methylpyridine dissolved in tetrahydrofuran was gradually added. The mixture was refluxed for 3 hours under "A saturated ammonium chloride solution was added _s, the reaction mixture was extracted with ether and the. organic phase was washed with sodium carbonate and dried over sodium sulfate. The ether was evaporated and the resulting 4 ~ £ (3-ethoxy-2-naphthyl) methyl / pyridine was dissolved in acetic acid and in a Parr apparatus in the presence of 1.5 g of platinum oxide touched. Hydrogen gas was initially introduced and the reaction continued until 0.3 mol of hydrogen was consumed. The solution was filtered and the solvent was removed in vacuo. The residue was dissolved in ether and excess dry HCl was bubbled through the solution to give 4 - [(3-ethoxy-2-naphthyl) methyl3piperidine hydrochloride.

Example 18 q- (3-Ethoxy-2-naphthyl) -4-piperidinemethanol hydrochloride

13.2 g of 4 - [(3-ethoxy-2-naphthyl) methyl] piperidine were added for 1 hour at 25 ^° C. under an atmosphere of oxygen

030034/0571

Stirred with 67 g of potassium t-butoxide in 2 _S 5 l of a solution of dimethyl sulfoxide and t "-butyl alcohol (4: 1). The reaction mixture was added to 4 l of water and the resulting solution was extracted with chloroform. The chloroform extract was mixed with water washed _s dried over magnesium sulfate and filtered, an excess of dry hydrogen chloride gas was bubbled through the chloroform solution _s giving a- (3-ethoxy-2-naphthyl) = 4-piperidinemethanol hydrochloride.

Example 19

4 - [* t- (2 -Naphthoyl) -1 -piperidyl 3-1-phenyl-1-butanone hydrochloride

A solution of 16 g (37 mmol) of 2-naphthyl-4-piperidylketon hydrochloride _s 13 g (71 mmol) of 4-chloro-l-phenylbutanons, Oji g of potassium iodide and 30 g of potassium bicarbonate in 100 ml of toluene at 48 hours with stirring heated in a steam bath »The mixture was partitioned between 100 ml portions of toluene and water and the organic phase was dried over magnesium sulfate» A solution of an excess of HCl in ether was added and the resulting precipitate was recrystallized from methanol / butanone _s whereby 4- (2 -Naphthoyl-l-piperidyl) -lphenyl-1-butanone hydrochloride was obtained. Melting point 197-199 ° C

Example 20

H- [U- (2-naphthoyl) -l ~ piperidyl] -l- (4-fluorophenyp-Ibutanone hydrochloride

Was used in the procedure of Example 19 in place of 4-chloro-1-phenyl-1-butanone 4-chloro-1- (4-fluorophenyl) -1-butanone used., so was 4- [4- (2-naphthoyl) -l-piperidyl] -

030034/0571

-JHf-

l- (4-fluorophenyl) -l-butanone hydrochloride produced. Melting point 252-253 ° C

Example 21

4-C4- (1-naphthoyl) -l-piperidyl3-1- (4-fluorophenyl) -lbut anon hydrochloride

In the procedure of Example 19, 4-chloro-1-phenyl-1-butanone was substituted for 4-chloro-1- (4-fluorophenyl) -l-butanone and 1-ketone hydrochloride in place of 2-naphthyl-4-piperidy l-naphthyl-4-piperidyl-ketone hydrochloride was used ₃ so 4- [4- (l-naphthoyl) -lpiperidyl3-l- (4-fluorophenyl) -l-butanone hydrochloride was prepared. Melting point 239-241 ⁰ C.

Example 22

3- [4- (4-Bromo-1-naphthoyl) -l-piperidyl3-1- (4-chlorophenyl) -1-propanone hydrochloride

In the procedure of Example 19, 4-bromo-1-naphthyl-4-piperidyl-ketone hydrochloride was used instead of 2-naphthyl-4-piperidyl-ketone hydrochloride and 3-chloro-1- (4-chlorophenyl) -1-propanone instead of ^ -chloro-1-phenyl-1-butanone 3-C4- (4-bromo-1-naphthoyl) -lpiperidylI- (4-chlorophenyl) -1-propanone hydrochloride was used manufactured.

Example 23

5- [4- (2-naphthoyl) -l-piperidyl3-1- (4-niethylphenyl) -lpentanone hydrochloride

030034/0571

Was in the method of Example 19 instead of 4-chloro-l-phenyl-l-butanone S-chloro-lC ^ -methylphe 1-peritanon _s used so 5- £ 4- (2-naphthoyl lpiperidylj-l- ^ -methylphenyD-l-pentanone hydrochloride produced.

Example 2fr

4- [il - ((4-chloro-1-naphthyl) methyl) -1-piperidy 13-1 phenyl-1-butanone hydrochloride

Was in the procedure of Example 19 4 l-naphthyl) methyl3piperidin hydrochloride instead of 2-naphthyl used ¹ l-piperidyl ketone hydrochloride _s so were 4- [4 - ((H-chloro-l-naphthyl) methyl) -l-piperidyl3-1-phenyl-l-butanone hydrochloride produced.

Example 25

phenyl) -1-butanone

A solution of 3 ^ S g (12 _S 5 mmol) of 6-chloro-2-naphthylil-piperidyl ketone hydrochloridj, 2 ₅ 63 g (13 ₃ 1 mmol) of fr-chloro-l-Cfr fluorphenyD-l-butanone , 2 _S 6 g (26 mmol) of potassium bicarbonate and a pinch of potassium iodide in 60 ml of toluene were refluxed for 80 hours. The mixture was partitioned between toluene and water and the organic phase was washed with brine _s gextfaschen dried over magnesium sulfate and concentrated in vacuo _s where ¹ l- [4- (6-chloro-2-naphthoyl) -lpiperidylj-l - ^ - fluorphenyD- l-butanone was obtained.

030034/0571

Example 26

4- [4- (6-chloro-2-naphthoyl) -1-piperidyl I- (4-fluorophenyl) -1-butanone methanesulfonate

The 4- [4- (6-chloro-2-naphthoyl) -1-piperidylJ-I- (4-fluorophenyl) -1-butanone prepared in Example 25 was used dissolved in acetonitrile and 0.6 ml (9j2 mmol) Methanesulfonic acid was added. The mixture was stirred for 5 minutes and concentrated in vacuo. The residue was stirred in anhydrous ether for 18 hours. The ether was decanted and the residue turned off Butanone and toluene recrystallized, with 4- £ 4- (6-chloro-2-naphthoyl) -1-piperidylJ-1- (4-fluorophenyl) -1-butanone methanesulfonate was obtained. Melting point 172-175 ° C.

Example 27

4-C4 - ((6-chloro-2-naphthyl) hydroxymethyl) -1-piperidyl3 ~ 1- (4-fluorophenyl) -1-butanone

Was used in the procedure of Example 25 instead of 6-chloro-2-napthyl-4-piperidyl-ketone hydrochloride α- (6-chloro-2-naphthyl) ^ 4-piperidinemethanol hydrochloride used, 4- [4 - ((6-chloro-2-naphthyl) hydroxymethyl) -1-piperidylI-1- (4-fluorophenyl) -1-butanone manufactured.

030034/0571

-W-

Example 28

4- [4 - ((6-chloro-2-naphthyl) hydroxymethyl) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone methanesulfonate

In the procedure of Example 26, instead of ¹ JC ¹ M 6-chloro-2-naphthoyl) -1-piperidyl] -1- (4-fluorophenyl) ~ 1-butanone was 4- [4 - ((6-chloro -2-naphthyl) hydroxymethyl) -lpiperidyl] -l- (4-fluorophenyl) -butanone was used _s so 4 ~ [4 - ((6-chloro-2-naphthyl) hydroxymethyl) -1-piperidyl] -l- ( ^! l-fluorophenyl) -l-butanone-inethanesulfonate produced "

Example 29

h-lH- ((2-Naphthyl) hydroxymethyl) -l-piperidyl] -l - (^ ~ fluorophenyl) -1-butanone

Was in the process of Example 25 a ~ (2-naphthyl) -4-piperidinemethanol hydrochloride used instead of 6-chloro-2-naphthyl-4-piperidyl ketone hydrochloride and the remaining solid was recrystallized from chloroform and ethanol so ⁱ 1- [4 - ((2-Naphthyl) hydroxymethyl) · 1-piperidyl] -l- (4-fluorophenyl) butanone produced "melting point 100-102 ⁰ C"

Example 30

4- £ 4 - ((1-naphthyl) hydroxymethyl) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone

V / was used in the procedure of Example 25 "- (1-naphthyl) - ^ J-piperidinemethanol hydrochloride in place of 6-chloro-2-naphthyl-4-piperidyl-ketone hydrochloride _{see above}

030034/0571

5fr

¹ I- [ ¹ M (l-napthyl) hydroxymethyl) -l-piperidyl] -l - (^ - fluorophenylj-l-butanone was prepared. Melting point 172-17 ¹ I ⁰ C.

Example 31

6- £ 4- (( ¹ -TrJf-fluoromethyl-2-naphthyl) methyl) -lpiperidyl3-1- (4-methoxypheny1) -1-hexanone

Was in the procedure of Example 25 4 - [(4-trifluoromethyl-2-naphthyl) methyl-3-piperidine hydrochloride instead of 6-chloro-2-naphthyl- ¹ l-piperidyl ketone hydrochloride and 6-bromo-l- (4- methoxyphenyl) -1-hexanone instead of ¹ I-ChIOr-I- (4-fluorophenyl) -l-butanone used, 6- [4 - ((ft-trifluoromethyl-2-naphthyl) methyl) -1-piperidyl3- 1 - (^ - methoxyphenyl) -1-hexanone obtained.

Example 32

q- (4-Fluorophenyl) -4 - [(6-chloro-2-naphthyl) hydroxymethyl 3 ~ l ~ piperidinebutanol

In the procedure of Example 25, instead of 6-chloro-2-naphthyl-4-piperidyl-ketone, a- (6-chloro-2-naphthyD-Jj-piperidinemethanol hydrochloride. And instead of ¹ -chloro-1- (4 -fluorophenyl) -l-butanone ¹ I-ChIOr-I- (Jj-fluorophenyDbutanol was used, then α- ( ¹ I-fluorophenyl) -4 - [(6-chloro-2-naphthyl) hydroxymethyl 3-1-piperidinebutanol manufactured.

030034/0571

Example 33

α- (4-Fluorophenyl) - ^ - (6-chloro-2-naphthoyl) -l-piperidinebutanol

In the procedure of Example 25, 4-chloro-1- (4-fluorophenyl) butanol was used in place of 4-chloro-1- (4-fluorophenyl) -l-butanone used, a ~ (4-fluorophenyl) -4- (6-chloro-2-naphthoyl) -1-piperidinbutanol was used obtain.

Example 34

q-Phenyl-4 - [(3-ethoxy-2-naphthyl) methyl3-1-piperidino-propanol

In the procedure of Example 25, instead of 6-chloro-2-naphthyl-4-piperidyl-ketone, 4 - [(3-ethoxy-2-naphthyl) methyl3piperidine and instead of 4-chloro-1- (4-fluorophenyl) -l-butanone If 3-bromo-1-phenylpropanol was used, then a-phenyl-4 - [(3-ethoxy-2-naphthyl) methyl] -1-piperidino-propanol was used obtain"

Example 35

3- [4- (8-Methyl-1-naphthoyl) -1-piperidyl3-1- (4-fluorophenyl) -1-propanone

A mixture of 25.5 g (O ₅ I mol) of 8-methyl-1-naphthyl-4-piperidyl ketone _s 9 g (O ₃ 3 mol) paraformaldehyde and 13.8 g (O ₅ I mol) 4'- fluoroacetophenone in 100 ml Isopropylalkoholj containing 2 drops of concentrated hydrochloric acid was heated _s 24 hours under reflux "the mixture was filtered and the filtrate was concentrated to about 100 ml

03 0.0 34/0571

concentrated and chilled. The resulting precipitate was recrystallized from ethanol to give 2- [4- (8-methyl-1-naphthoyl) piperidyl [-l- ( ^ -fluorophenyl) -1-propanone].

Example 36

3 ~ [^ - ((4-Bromo-1-naphthyl) hydroxymethyl) -1-piperidylI-1- (4-fluorophenyl) -1-propanone

When a- (JJ-Bromo-1-naphthyl) -4-piperidinemethanol was used in place of 8-methyl-1-naphthyl-piperidyl-ketone in the procedure of Example 35, <% - [4 - ((4-bromo -l-naphthyl) hydroxymethyl) -l-piperidylI-l- (4-fluorophenyl) -1-propanone was obtained.

Example 37

piperidine butanol

8.1 g (0.02 mole) 4- [4- (2-fiaphthyl) hydroxymethyl) -lpiperidylI-1- (4-fluorophenyl) -l-butanone HCl in 50 ml of methanol were mixed with 1.1 g (0.02 mol) of sodium methoxide and then 2.7 g (0.05 mol) of potassium borohydride were added, and the mixture was allowed to stand at room temperature for 2 hours touched. The methanol was removed on a steam bath under reduced pressure, after which 50 ml of 10% strength Sodium hydroxide solution was added. The mixture was stirred for 15 minutes and 100 ml of chloroform was added. Stirring was continued for 1/2 hour. The chloroform layer was separated and mixed with two 25 ml chloroform extracts the aqueous phase combined with water

030034/0571

washed with brine, dried over magnesium sulfate, filtered and concentrated to a solid "The solid material was _s recrystallized from ethanol / water with a - (^ - Pluorphenyl) -4 - [(2-naphthyl) hydroxymethyl] -1-piperidinebutanol obtained became.

Example 38

i & -Phe nyl-4 - [(4-chloro-1-naphthyl) methyl3-1-piperidinebutanol

In the procedure of Example 37, instead of ii- [4- (2-naphthyl) hydroxymethyl) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone was 4- [4 - ((4-chloro-l -naphthyl) methy2> 1-piperidyl ^ -l-phenyl-l-butanone hydrochloride was used , e-phenyl-Jj-t ^ -cfolor-l-naphthyDmethyl] -! - piperidinbutanol was obtained,

Example 39

ffi- (fluorophenyl ) -4-C (6-chloro-2-naphthyl) hydroxymethyl] -1-piperidinbut anol

A suspension of 4 _S 4 g (O _S O1 mol) 4- [il- (6-chloro-2-naphthoyl) -l-piperidyl3-1- (4-fluorophenyl) -1-butanone in 100 ml of absolute ethanol was added stirring at 50 ⁰ C gradually with 1 ₃ 9 g (0 _a 05 mol) of sodium borohydride "the stirring was continued for 1 hour at 50 ° C after completion of addition and 20 ml of 3N hydrochloric acid was added slowly» the mixture was diluted with water to 400 ml diluted, basified with sodium hydroxide and extracted with chloroform »The organic layer was _s dried over magnesium sulfate concentrated in vacuo and recrystallized ₉ wherein β- (Jj-fluorophenyl) - * - [(6-chloro-2-naphthyl) hydroxymethyl] -l-piperidinbutanol obtained vmrde.

030034/0571

Example 4P

q- (4 -Fluorophenyl) -4 - [(8-methyl-1-naphthyl) hydroxymethyl j-1-piperidine propanol

In the procedure of Example 39, 3 ~ [4- (8-Methyll-naphthoyl) -l-piperidylI-1- (4-fluorophenyl) -l-propanone instead of 4- [4- (6-chloro-2-naphthoyl) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone was used, so was α- (4-fluorophenyl) -4 - [(8-methyl-1-napthy1) hydroxymethylJ-1-piperidine propanol obtain.

Example 41 Tablet formulation

An example of a representative tablet formulation an effective compound according to the invention is the following:

Per tablet

(a) 4 - [(4- (l-Naphthyl) hydroxymethyl) -1-piperidyl] -l- (4-fluorophenyl) -1-

butanone 25.0 mg

(b) Wheat starch 3 ₃ 5 mg

(c) lactose 10.0 mg

(d) Magnesium stearate 0.5 mg

Granulation was obtained after mixing by Laie nasty with the starch paste and the granulated starch paste was dried, sieved and mixed with the active ingredient and magnesium stearate = the mixture was pressed into tablets, each weighing 39 _s 0 mg.

030034/0571

Example 42 Gelatin capsule

An illustrative mix for hard gelatin capsules is the following:

mg

(a) 4 - [(4- (2-Naphthoyl) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone hydrochloride 10

(b) Talk 5

(c) lactose 100

The formulation was prepared by ₅ the dry powder of component (a) and (b) were forced through a fine mesh sieve and were mixed together well ο The powder xfurde into hard gelatin capsules to a net fill weight of 115 mg per capsule filled.

Example 43 Injectable suspension

An illustrative mixture for an injectable suspension provides the following 1 ml ampoule for an intramuscular Injection:

Weight -%

(a) 4 - [(4- (1-Naphthyl) hydroxymethyl) ~ 1-piperidy1 2 ~ 1- (4-fluorophenyl) -

1-butanone (particle size ^ 10 / u) l _s 0

(b) polyvinylpyrrolidone (molecular

weight 25000) O ₅ 5

(c) lecithin O ₅ 25

(d) V / water for injection to make 10O ₅ O

030034/0571

The ingredients (a) - (d) were mixed, homogenized and filled into 1 ml ampoules, which sealed and Treated in an autoclave at 121 ° C for 20 minutes. Each ampoule contained 10 mg per ml of the compound (a) according to the invention.

For: Richardson-Merrell Inc., Wilton, Conn., V.St.A.

Dr. K.JCKr. Beil lawyer

ά k . 0 5 7 1

Claims (1)

Ί ^. Jan. 0 FRANKFURT depreciation MMU 80
Patent claims: 1. Compound of the general formula wherein η is a whole number from 2 to 5 _• R represents a hydrogen atom _a is a Halogenatonij a straight or branched chain alkyl of 1 to 4 carbon atoms, a straight or branched alkoxy group having 1 to 4 carbon atoms or a trifluoromethyl radical _s R ₁ is a ¥ asserstoffatom _a a Halogen atom _{s is} a straight or branched chain alkyl group with 1 to 4 carbon atoms or a straight or branched chain alkoxy group with 1 to 4 carbon atoms ^ X is a carbonyl group, a hydroxymethylene group or a methylene group and Z is a carbonyl group or a hydroxymethylene group _{s is} a single diastereomer or optical isomer or a pharmaceutically acceptable acid addition salt thereof = 2. A compound according to claim 1, characterized in that Z is of formula ₅ 'is a carbonyl radical. 3 »A compound according to claim l _{s s} characterized in that X of Formula represents a carbonyl or hydroxymethylene. 4. A compound according to claim 1, characterized in that η _s of formula 3. 0 30 034/057 1 5. A compound according to claim 1, characterized in that R _{1 of} the formula is a halogen atom. 6. A compound according to claim 5 _S, characterized in that R _{1 of} the formula is a fluorine atom. 7. A compound according to claim 1, characterized in that R of the formula represents a hydrogen atom or a halogen atom. 8. ^ -A- (2-naphthoyl) -l-piperidyl7-l- ( ⁱ -fluorophenyl) -lbutanone or a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 1. 9. ^ - / '4- (1-naphthyl) -hydroxymethyl) -l-piperidyl7-1- (4-fluorophenyl) -l-butanone or a pharmaceutically acceptable acid addition salt thereof as a compound of claim 10. il-A-d-NaphthoyD-l-piperidylj'-l-C ^ -fluorophenyD-l-butanone as a compound according to claim 1. 11. i | -A- (6-chloro-2-naphthoyl) -l-piperidyl7-l- ( ^j »-fluorophenyl) -1-butanone or an acid addition salt thereof as a compound according to claim 1. 12. A compound according to claim 1, characterized in that Z of the formula is a hydroxymethylene radical. 13. Compound of the general formula 030034/0571 wherein R is a hydrogen atom, _{s is} a halogen atom, _{s is} a straight or branched-chain alkyl radical with 1 to H carbon atoms, a straight or branched-chain alkoxy radical with 1 to 4 carbon atoms or the trifluorinated methyl radical and X is a carbonyl _{radical, s is} a hydroxymethylene radical or a methylene radical, where, when X is a Carbonyl radical means that R does not represent a hydrogen atom, _s an individual optical isomer or an acid addition salt thereof. l4o compound according to claim 13 or an acid addition salt thereof _s characterized _s that X of Formula represents a carbonyl " 15. A compound according to claim 13 or an acid addition salt thereof. Wherein X _s that is of the formula a hydroxymethylene. 16. A compound according to claim 13 or an acid addition salt thereof, characterized in that X is of the formula _s is a methyl radical meant 17. ö-chloro-S-napthyl - ^ - piperidyl ketone or an acid addition salt the same as a connection according to claim 13 » 18. oi- (1-naphthyl) - ^ - piperidinemethanol or an acid addition salt the same as a compound according to claim 13 ° 030034/0571 19. Process for the preparation of a compound according to claim 1, characterized in that one a) a compound of the general formula 030034/0571 wherein j in claim l ^a meaning given own ₉ in a suitable solvent in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide of about 2 hours to 96 hours at a temperature of etwa.20 to 18O ° C with a compound of formula Halo- (CH ₂ ) _n - wherein halo is a chlorine atom, _{s is} a bromine atom or an iodine atom and n _s Z and R ^ have the meanings given in claim 1., alkylated or b) when X and Z .both mean a hydroxymethylene radical, a compound according to claim l _s where Z of the formula is a carbonyl radical and X of the formula is a carbonyl radical or a hydroxymethylene radical, _{s is} reduced or c) if X is a methylene radical and Z is a hydroxymethylene radical, a compound according to claim l _s wherein X of the formula is a methylene radical and Z of the formula is a carbonyl radical, reduced, and d), in the case of a pharmaceutically acceptable acid addition salt, reacting the compound so obtained with a pharmaceutically acceptable acid. 20. Process for the preparation of a compound of the general formula H
wherein X is a carbonyl radical, a hydroxymethylene radical or a methylene radical and R _{2 is} a hydrogen atom, 030034/0571 a halogen atom, a straight or branched alkyl radical with 1 to 4 carbon atoms or a straight or branched alkoxy radical with 1 to H carbon atoms, where, when X is a carbonyl radical, R_ is not a hydrogen atom, and furthermore, when R _? has a meaning other than a hydrogen atom, the remainder of the formula NH and R ₂ are bonded to the 1,4, 1,2, 2,6 or 1,7 positions of the naphthalene ring, or an acid addition salt thereof, characterized in that one. a) a naphthalene derivative of the general formula in the presence of a suitable solvent and an excess of a Lewis acid 10 minutes to 6 hours' at a temperature of 0 to 90 C with a 4-piperidine carbonyl halide salt the formula 0
C-HaIo H · Halo where halo means a chlorine atom or a bromine atom, acylated and subsequently makes the solution basic, b) when X of the formula is a hydroxymethylene or a Methylene radical means that the acylated product thus obtained is selectively reduced and 030034/0571 c) in the case of a salt, the compound thus obtained is reacted with a suitable acid " ο A process for preparing a compound according to claim 13 wherein _{s 3} that a) a Grignard reagent of the general formula MgY wherein R has the meaning given in claim 13 and Y represents a bromine atom or an iodine atom _s about 2-8 hours with a pyridine derivative of the general formula wherein Q is a CHO- ₉ CN- or CH ₂ -HaIo-ReSt and halo is a chlorine atom, a bromine atom or an iodine atom _{3 is} heated under reflux and the resulting reaction mixture is treated with an aqueous ammonium chloride solution _s b) the product thus obtained is selectively reduced ₃ where, if Q is a radical of the formula CHp-Halo, a compound according to claim 1 in which X is a methylene _{radical s} and if Q is a radical of the formula CHO or CN, _{s is} a compound according to claim 1 _s where X is a hydroxymethylene radical or a methylene radical _{s is} produced _s c) if X is a carbonyl radical, _{s is} a compound obtained in this way according to claim 13 _s in which ^{x is} a hydroxymethylene radical, _{s is reacted} with a suitable oxidizing agent and 030034/0571 S. - ζ - d) in the case of a salt, reacting the product thus obtained with a suitable acid. 22. A pharmaceutical preparation containing a compound according to claim 1 and a pharmaceutical carrier. 23. Antipsychotic preparation containing an antipsychotic effective amount of a compound of claim 1 and a pharmaceutical carrier. 2'h. Preparation according to claim 22 or 23, characterized in that it contains from 0.5 to 200 mg of the compound in the form of a dosage unit. 25. Preparation according to claim 22 to 2k _t characterized in that the compound according to claim 1 ⁱ lA- (2-K ^T aphthoyl) -l-piperidyl / -l - (^ - fluorophenyl) -l-butanone, 4-Z " 4 - ((l-naphthyl) · hydroxymethyl) -l-piperidyl / -l- ( ⁱ l-fluorophenyl) -1-butanone or a pharmaceutically acceptable acid addition salt thereof. 030034/0571